The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice
Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function.
Rkip1 (also known as Pebp1) knockout (Rkip1 −/−) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment.
Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.
These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.
- The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice
Volume 55, Issue 12 , pp 3331-3340
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- Beta cell
- Neonatal beta cell growth
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- Author Affiliations
- 1. Laboratory of Diabetes and Obesity, IDIBAPS, Centre Esther Koplowitz, 5th Floor, Rosselló, 153, 08036, Barcelona, Spain
- 2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain www.ciberdem.org/
- 3. Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
- 4. Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- 5. Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- 6. Umeå Centre for Molecular Medicine (UCMM), Umeå University, Umeå, Sweden
- 7. University of Barcelona, Barcelona, Spain